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Despite extensive characterisation of immune responses across peripheral organs, the immunological landscape of the central nervous system (CNS) remains incompletely defined. Among the resident immune cell populations in the brain, mast cells and microglia have emerged as key modulators not only of neuroinflammatory processes but also of fundamental homeostatic functions, including regulation of sleep, affective states, and energy balance. These cells engage in complex bidirectional communication, mediated in part by the biogenic amine histamine. Although histamine was first identified over a century ago, its multifaceted roles in CNS homeostasis, immune surveillance, and neuropathophysiology remain poorly delineated. This review examines the biosynthesis, receptor-mediated signalling, and functional consequences of histaminergic activity within the brain, with a particular focus on microglial dynamics. We discuss crosstalk between mast cells and microglia via histamine signalling pathways, and the potential implications of this interaction in the etiology of neurodevelopmental disorders. Furthermore, we evaluate the emerging evidence on the capacity of centrally acting antihistamines, especially those capable of penetrating the blood-brain barrier, to modulate microglial phenotypes. Collectively, these insights underscore the urgent need for deeper mechanistic studies to elucidate histamine's role in CNS immunophysiology.